Breast cancer risk is higher in nulliparous than in parous women whose first pregnancy occurred at an early age. It has been shown that induction of carcinomas of the rat mammary gland by exposure to 7,l2-dimethylbenz(a)anthracene (DMBA) is prevented if the exposure is preceded by pregnancy and lactation. Studies from our laboratory have demonstrated that differentiation of the gland and the growth state of the cells, brought about through pregnancy and lactation, is responsible for the refractoriness of the parous gland to DMBA carcinogenesis. Our evidence suggests that this rat system can provide an excellent model for exploring the mechanisms involved in diminished susceptibility of breasts of parous women to carcinogenesis. The proposed studies will determine whether the different susceptibilities of virgin and parous rat mammary gland to DMBA are due to variations in the metabolism, differences in the DNA binding capacity, and/or the generation of different DMBA-DNA adducts after exposure of the cells to DMBA under both in vitro and in vivo conditions. The data from these studies will be important for understanding the observed differences between tumor incidence in virgin and parous rats following DMBA administration, and elucidating the mechanism of protection conferred by pregnancy and lactation.